1. Field of the Invention
The present invention relates generally to the fields of peptide chemistry and molecular pathology and, more specifically, to novel peptides which bind to calmodulin.
2. Background Information
Calcium is one of the "second messengers" which relays chemical and electrical signals within a cell. This signal transduction and, hence the regulation of biological processes, involves interaction of calcium ions with high-affinity calcium-binding proteins. One such protein is the ubiquitous intracellular receptor protein calmodulin.
Upon calcium binding, calmodulin interacts with a number of protein targets in a calcium dependent manner, thereby altering a number of complex biochemical pathways that can affect the overall behavior of cells. The calcium-calmodulin complex controls the biological activity of more than thirty different proteins including several enzymes, ion transporters, receptors, motor proteins, transcription factors, and cytoskeletal components in eukaryotic cells.
Since calmodulin plays such a fundamental role in cell biology, agents that inhibit or alter its action can have important pharmacological effects. Further, an understanding of the mechanism by which these drugs alter calmodulin-dependent actions can suggest new pharmacological approaches to alter physiological or pathological processes. The discovery of selective pharmacological agents that interfere with the actions of calmodulin can provide a means to explore the physiological role of the calcium-binding protein and can provide new therapeutic agents.
A number of calmodulin targeted compounds are known and used for a variety of therapeutic applications. For instance, chlorpromazine ("THORAZINE".RTM.) and related phenothiazine derivatives, disclosed, for example, in U.S. Pat. No. 2,645,640, are calmodulin antagonists useful as tranquilizers and sedatives. Naphthalenen-sulfonamides, also calmodulin antagonists, are known to inhibit cell proliferation, as disclosed, for example, in Hidaka et al., PNAS, 78:4354-4357, (1981) and are useful as antitumor agents. In addition, the cyclic peptide cyclosporin A ("SANDIMMUNE".RTM.), disclosed in U.S. Pat. No. 4,117,118, is as an immunosuppressive agent which is thought to work by inhibiting calmodulin mediated responses in lymphoid cells.
Many of the known calmodulin inhibitors have additional, undesirable biological effects when administered at concentrations sufficient to block calmodulin. The undesirable effects are usually negative side effects, such as toxicity, or non-specific binding to other proteins or receptors, as described, for example, in Polak et al. J. Neurosci., 11:534-542. (1991). A specific example is the toxic side effects from cyclosporin A. Therefore, a need exists for calmodulin targeted agents, and in particular calmodulin antagonists which inhibit calmodulin without having additional, undesirable biological side effects, and especially ones which do not have toxic side effects. This invention satisfies these needs and provides related advantages as well.